This invention relates to a class of target-specific small molecules used as active pharmaceutical ingredients, capable to interact with their respective sub-units to build binding motifs and their specific interaction and dynamic diffusion behavior with polyester excipients of the Poly-Lactide-Glycolytes and their different applied forms, building a specific dosage form during the injection into body-fluids and body-tissues and the specific pharmacokinetic, pharmaceutical production and medical use advantages especially in combination therapies with other oral or injected pharmaceutical actives or functional dosage forms targeting RNA and DNA or physiological RNA- and DNA-Protein complexes occurring in cellular disease processes.
Immunodeficiency syndrome (AIDS) has its cause in the acquired infection by HIV (Barre-Sinoussi et al., 1983, Science 220:868-870; Gallo et al., 1984, Science 224:500-503). Genetic heterogeneity exists within each of the therapeutically recognized HIV subtypes.
The Virus, typically a genetically polymorphic retroviral RNA-encoded subset infects Immune Cells, the incorporation into the cell and the virus copying processes use cellular human as well as HIV-encoded proteins and enzymes. Two classes of enzymes synthesize the DNA (reverse transcriptase, RT) using the virus RNA and Integrase using the DNA copies to be integrated in the human chromosomal DNA.
The WHO promoted standard therapies inhibit these two enzymes with different molecular binding strategies of synthetic small molecule APIs.
Oral small molecule therapies found their optimal application by using simple immediate release formulation of three such APIs eventually boosted by similar liver enzyme to improve First Pass effects of liver metabolizing the drug before reaching the infected cell's disease target. E.g. in single, double and triple-tablet daily dosing protocols well tolerated e.g. Lamivudine+Efavirenz+Tenofovir and Lamivudine+Zidovudine+Abacavir using both nucleoside/nucleotide-type (NRTIs) and non-nucleoside type (NNRTIs) reverse transcriptase inhibitors with oral doses trypically above 100 mg and below 1 g each per dose.
Recently the therapy spectrum was enlarged by the use of RT- and integrase-inhibitors with again small molecule structures however targeting the DNA-complexes in proximity to the substrate-pocket of the enzyme protein. Those inhibitors are so well tolerated and still high potent so that oral dosing is below 100 mg, injected doses far below 100 mg are reported therapeutically active. This class of compounds are effective in man and introduced as injectable and reported to speculative depot formulation tests. The disadvantages of depot formulations today are the sophistication of processes, such as precision molding and (micro-)encapsulation or macroscopic implant medication.
Epidemiological theory demands to individually lower constantly the serum positive patient's body fluid as well as cellular copy numbers to avoid resistance response via natural error-prone selection of Virus mutations. This stabilizes the virus population in the regime of the treatment for both the individual and the population fate of such devastating resistance and a niche adoption of natural human population is at risk. This is why intervention strategies need options of drugs and drug regime compliance and adherence that are beyond practical reach with oral medication today.
It was the aim of this invention to solve the dilemma that regions with highest HIV infection numbers and rates need common denominator drug combination with lowest prize, highest efficiency individually and best viral niche adaption epidemiologically in the sense that an inbound adherence would allow for rate deflation of new infections Male workers, with income, women, pregnant women and child, girls and newborns using WHO accepted therapy standards technically not established today.
Arts et al. explain on the HIV database HIV Databases www.hiv.lanl.gov/ (last modified 2013) with in vivo and in vitro data the differences of RT-resistance using NNRTIs and NRTIs the latter predominantly binding to the substrate pocket would lead to short quasi-type resistance preservation in order to re-establish virus fitness whereas NNRTIs bind to a lipophilic pocket allosterically changing the enzyme activity, mutations which could be tolerated after release from the drug-selection pressure. The usefulness of the drug depot described here relates to this: the virus is cornered in choices dilemmas and well-tolerated drugs such as AZT (Zidovudine) would oscillate in regime whereas a drug component with long pharmacokinetic tailing would keep one exit closed to escape during virus-cyclic mutations. This is one reason why the very discrete mutation pattern with low cross-resistance between the NNRTIs and the NRTIs lead to less fit viruses compared to the pattern collection in the protease enzyme and a superior medication track record of such combinations. These combination therapies are high genetic barrier therapies. Integrase Inhibitors (II), dolutegravir. Linos Vandekerckhove et al. conclude however in PLOS (2013) that in first-line therapy, integrase inhibitors are superior to other standard regimens. Integrase inhibitor use after virological failure is supported as well by their meta-analysis of 48 clinical studies. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment. This would translate into a therapy naive patient strategy with one or two NRTI or one NRTI and one NNRTI as per the low cost solution in Lamivudine and AZT and a depot injection as disclosed.
U.S. Pat. No. 5,278,201 (Dunn et al.) describes biodegradable in-situ forming implants and methods of producing the same. A poly(D,L-lactic acid) formed by polycondensation is dissolved in NMP (N-methyl-2-pyrrolidone) at a ratio of 68:32 polymer to solvent. Sanguinarine, a benzophenanthridine alkaloid with antimicrobial activity, was added to the solution at a concentration of 2% by weight. In a drug release-test 60% of the drug was released in the first day.
U.S. Pat. No. 8,470,359B2 (Dunn et al.) describes sustained release polymers. In an example a 75/25 lactide to glycolide copolymer was dissolved in N-methyl-2-pyrrolidone at a ratio of 45/55.